DESCRIPTION Inhibited immune responses have been observed following occupational, inadvertent, or therapeutic exposure to xenobiotics. Further, aberrant immune responses (e.g., hypersensitivity, autoimmunity) appear to be increasing in humans, a phenomenon which may be related to environmental chemical exposure. New research initiatives are determining that such exposures, often previously considered to be innocuous, may in fact be contributing to impaired human immune health. The present proposal considers immunotoxicity resulting from combined dermal exposure to a common pyrethroid insecticide (permethrin) and to cis-urcanic acid (cUCA, an isomerization product of trans-UCA and sunlight). Preliminary data have been generated showing both systemic and regional immunotoxicity from low-level topical permethrin (formerly not considered an immunotoxicant). It has previously been demonstrated that cUCA also inhibits skin and immune responses. The proposed studies will estimate the risk of immunotoxicity from combined topical permethrin and intradermal cUCA exposure, using National Toxicology Program-approved testing procedures in C57B1/6 inbred mice. These immunotoxicants will also be co-administered at levels determined to inhibit immune responses in mice, to investigate cytokine-dependent mechanisms by which cUCA and/or permethrin may cause suppression of immunity. Further, in that: 1) cUCA has been shown to inhibit antigen presentation by macrophages, 2) new data suggest the epidermal antien presenting cell (APC, Langerhans cell [LC]) may be a target of cUCA, and 3) permethrin was shown by us to inhibit skin contact hypersensitivity responses, the effect of single and combined exposure to these agents on antigen presentation by LC will be examined as a mechanism related to immunotoxicity. Providing new data to assist the estimation of risk from the combined immunotoxicant exposure (cUCA and topical insecticide) in children is a primary goal of the proposal.